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The effect of dose and gender on the pharmacokinetics (PK) and pharmacodynamics (PD) of zolpidem after administration of a buffered zolpidem sublingual tablet (ZST; Intermezzo®, Purdue Pharma L.P., Stamford, CT, USA) was evaluated in healthy non-elderly male and female volunteers. Subjects received a single morning dose of ZST (1.0, 1.75, and 3.5 mg) or placebo in a four-way crossover study. In male and female subjects zolpidem PK were linear, with area under the curve (AUC) proportional to dose, and apparent oral clearance and elimination half-life independent of dose. However, AUC averaged 40% to 50% higher in females than in males receiving the same dose. The gender effect was incompletely explained by body weight. In females, ZST produced PD changes consistent with benzodiazepine agonist effects, particularly at the 3.5-mg dose. For several PD variables, PD effects were significantly related to plasma zolpidem concentrations when data were aggregated across subjects. However, there was variability in response among individuals. In males, PD effects of zolpidem seldom differed from placebo regardless of plasma concentration. The findings confirm that zolpidem clearance is lower in females than in males. PD effects of zolpidem from ZST are greater in female subjects, due to a combination of higher plasma concentrations and greater intrinsic sensitivity.

Serotonin and dopamine neuronal systems have been implicated in the modulation of obsessive-compulsive disorder (OCD) symptoms. About 40% of OCD patients do not respond to first-line selective serotonin reuptake inhibitor (SSRI) treatment; among those, dopamine blocker augmentation has been reported to improve the rate of response by an additional one-third. Given that serotonin 5-HT(3) receptors are indirect inhibitors of cortico-mesolimbic dopamine release, augmentation with the 5-HT(3) receptor antagonist ondansetron in combination with SSRIs and antipsychotics has potential efficacy in treatment-resistant OCD patients. To assess the efficacy and tolerability of ondansetron in combination with SSRIs and antipsychotics in patients with treatment-resistant OCD. In total, 14 patients with a DSM-IV diagnosis of OCD, who were treatment resistant and receiving stable treatment with SSRIs and antipsychotic augmentation, entered a 12-week, single-blind trial of ondansetron. The drug was initiated at a dosage of 0.25 mg twice daily for 6 weeks and was then titrated to 0.5 mg twice daily for 6 weeks. Of the 14 patients, nine (64.3%) experienced a treatment response (> or =25% reduction in the Yale-Brown Obsessive Compulsive Scale [YBOCS] score and a Clinical Global Impressions-Improvement [CGI-I] score of 1 or 2) at 12 weeks. The average reduction in YBOCS-rated symptoms for the whole group was 23.2%. None of the treated patients experienced symptom exacerbation or significant adverse effects. These results suggest that low-dose ondansetron may have promise as an augmentation strategy for some patients with OCD resistant to SSRIs and antipsychotic augmentation, but further controlled trials are required. Trial registration number (ClinicalTrials.gov): NCT00796497.

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